Testosterone, historically believed to be important only for male reproduction and sexuality, has over the past decades transformed from niche hormone to multi-system player.1 A rapidly accumulating body of research is showing that testosterone is an important metabolic hormone with marked effects on energy metabolism and body composition.2

In the USA, 36% of the adult population are obese (BMI >30), (affecting a similar proportion of men and women)3, and obesity prevalence is escalating worldwide. According to the McKinsey Global Institute (MGI) report “Overcoming obesity: An initial economic analysis”, obesity is “one of the top three preventable social burdens (along with smoking and violence/war/terrorism) generated by human beings” imposing an estimated annual global direct economic burden amounting to 2 trillion USD.4

Obesity treatments with comprehensive lifestyle modification and/or drugs are notorious for their poor long-term efficacy and inability to achieve long-term weight loss maintenance.5-9 Even with continued lifestyle treatment, significant weight regain occurs.7,9,10 And obesity drugs have side effects which limit their long-term and widespread use.11,12 Therefore, new interventions are urgently needed to combat this alarming preventable threat to society.

In this editorial we present a recent study by Saad et al., which investigated the effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III.13

Key Points

Testosterone therapy for up to 8 years results in progressive, continuous and sustained reduction in body weight, waist circumference and BMI, regardless of obesity grade and age.

Treating obese hypogonadal men with testosterone for 8 years is safe. Elevations in PSA and hematocrit stayed within normal ranges, and the incidence of prostate cancer is lower than expected from the prostate cancer incidence reported in the general population of men not treated with testosterone.

Using testosterone therapy as a mode of obesity treatment may result in greater beneficial effects on body composition than diet and/or drug induced weight loss.

What is known

Obesity is the underlying driver of many chronic diseases and weight loss improves health, particularly cardio-metabolic risk factors14 and reduces healthcare costs.15 Although lifestyle changes with diet and exercise are considered the first step in obesity treatment, by themselves lifestyle changes are inadequate for obesity treatment and successful long-term maintenance of weight loss.5-9

Obesity is a risk factor for incident testosterone deficiency and its consequences16; an excessive amount of body fat suppresses the HPT (hypothalamic-pituitary-gonadal) axis and thereby reduces testosterone production by multiple mechanisms; via increased insulin resistance, metabolic syndrome and diabetes17,18, and elevation in estradiol and cortisol levels.19,20 In line with this, cross-sectional analyses show that obese men have lower testosterone levels than age-matched non-obese men.21,22 Strikingly, the prevalence of testosterone deficiency in severely obese men may be as high as almost 80%.23 In the prospective Massachusetts Male Aging Study (MMAS), non-obese men who became obese had a decline of testosterone levels comparable to that of 10 years of aging.24 Another prospective study confirmed that weight gain results in a proportional decrease in testosterone levels at follow-up.25

Many intervention studies show that testosterone therapy in obese men with testosterone deficiency reduces fat mass and increases lean body mass with concomitant WL, reduction in waist circumference (WC) and body mass index (BMI).26-30 Notably, long-term testosterone therapy for up to 6 years in obese men with testosterone deficiency results in a significant and marked weight loss, and reduced waist circumference and BMI.27,31-34 Importantly, testosterone therapy results in sustained weight loss without recidivism and weight regain.32-34

Thus, it is possible that testosterone therapy in obese men with testosterone deficiency may prove useful in treatment of the underlying pathophysiological conditions of obesity. Support for this comes from experimental studies demonstrating that testosterone is an important metabolic hormone2 that increases fat oxidation.35-37 Accordingly, testosterone therapy in hypogonadal obese men has been suggested as a novel approach for the treatment of obesity.38,39

All 411 obese, hypogonadal men received testosterone therapy in urological clinics, which comprised two independent observational registries. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. Figure 1 illustrates how the treatment elevated testosterone levels, which are also given numerically in table 1.

In all three classes of obesity, testosterone therapy resulted in significant weight loss and decrease in waist circumference and BMI, as outlined in the table 1.

Table 1: Changes in obesity parameters and total testosterone levels.

Class I obesityBMI 30–34.9

Class II obesity35–39.9

Class III obesityBMI ⩾ 40

Total testosterone

+8.16 nmol/L(from 8.74 to 17.02* nmol/L)

+7.29 nmol/L(from 9.3 to 16.86* nmol/L)

+6.41 nmol/L(from 9.34 to 15.99* nmol/L)

Free testosterone

+235 ng/dL(from 252 to 491* ng/dL)

+210 ng/dL(from 268 to 486* ng/dL)

+185 ng/dL(from 269 to 461* ng/dL)

Body weight

-17.4 kg or -16.8%(from 102.6 kg to 84.1 kg)

-25.3 kg or -21.5%(from 116.8 to 91.3 kg)

-30.5 kg or -23.6%(from 129.0 to 98.9 kg)

Waist circumference

-10.6 cm(from 106.8 to 95.1 cm)

-13.9 cm(from 113.5 to 100.0 cm)

-14.3 cm(from 118. 5 to 103.8 cm)

BMI

-5.52(from 32.69 to 27.07)

-8.15(from 37.32 to 29.49)

-9.96(from 41.93 to 32.46)

* Note: When interpreting the elevations in testosterone levels (total and free), one has to bear in mind that these reported levels are trough levels, i.e. the lowest level measured immediately before the next injection. Pharmacokinetic data show that after one injection of testosterone undecanoate it takes 9 days to reach Cmax (concentration maximum, i.e. the peak level) at 32.0±11.7 nmol/L, and 70.2 days for half of the injected testosterone dose to be eliminated from the body (i.e. t½ = elimination half-life, is 70.2 days).40 Mean levels in the lower normal range – but significantly higher compared with baseline values – can be maintained until approximately 12 weeks after one injection.40 While these pharmacokinetic data were derived in non-obese men - and will likely differ in obese men – it does give a rough guideline when interpreting testosterone levels during testosterone treatment.

All obesity groups also experienced significant improvements in metabolic parameters; glycemic control (fasting glucose and HbA1c), lipids (total cholesterol, LDL, HDL, triglycerides and total cholesterol:HDL ratio), liver transaminases, inflammation and blood pressure (both systolic and diastolic) all improved. This was accompanied by a marked and significantly increased quality of life, regardless of obesity class.

Subgroup analyses to assess the effectiveness of testosterone therapy in patients ⩽ 65 years old (n = 323) and in patients >65 years old (n = 88) showed that testosterone therapy is equally effective in improving obesity and metabolic parameters, as well as quality of life, irrespective of age.

Testosterone therapy in obese men increased hemoglobin and hematocrit but the levels remained within physiological ranges. There were no major adverse cardiovascular events. Prostate volume increased in all men regardless of obesity grade, but there were no cases of urination problems. In fact, lower urinary tract symptoms (assessed by the IPSS scale) decreased. As expected, PSA levels increased in all men (regardless of obesity grade) but the increase stayed within normal range and was not clinically significant. 8 patients were diagnosed with low-grade prostate cancer while on testosterone treatment. Notably, this represented only 1.9% of treated men, and is far less than the prostate cancer incidence reported in the general population of men not treated with testosterone. For more information, see our previous editorial “Incidence of Prostate Cancer in Hypogonadal Men Receiving Testosterone Therapy for up to 17 years”.

It was concluded that testosterone therapy is a safe and effective treatment to achieve sustained weight loss in obese hypogonadal men irrespective of severity of obesity.

Comparison to traditional obesity treatments

The improvements in obesity parameters in this study markedly outperform those seen with traditional obesity treatments. For example, a comprehensive program of lifestyle modification can produce a 7% to 10% reduction of body weight.41 The weight loss achieved in the study by Saad et al. amounted to 16.8% to 23.6%.

A systematic review of long-term weight loss studies in obese adults found that diet/lifestyle treatment produces <5 kg weight loss after 2-4 years, pharmacologic treatment 5-10 kg weight loss after 1-2 years, and surgical treatment 25-75 kg weight loss after 2-4 years.6 As demonstrated in the study by Saad et al., testosterone therapy results in weight loss far exceeding that of both diet/lifestyle therapy and traditional drug therapy. Only surgical treatment results in greater weight loss, but it is not without risks.

Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year.3 While a weight loss of 9% after 1 year may seem large, the long-term safety and efficacy of phentermine + topiramate is unknown.

The Look AHEAD trial, which investigated the long-term effects of a lifestyle intervention on weight found a weight loss of -6.15% after 4 years.42 In the study by Saad et al. weight loss at the 4 year mark ranged from -10% to -15%, depending on obesity grade. Notably, an 8 year analysis of The Look AHEAD trial - with subjects having a baseline BMI of 35 (the same as in the study by Saad et al.) - reported a weight loss of 7.9, 3.7, and 4.0 kg for years 1, 4, and 8, respectively. The corresponding weight loss in men on testosterone therapy in the study by Saad et al. was 3, 10.7, and 17.4 kg in class I obese men, 3.8, 16.6, and 25.3 kg in class II obese men, and 3.5, 18.5, and 30.5 kg in class III obese men, as outlined in table 2.

When looking at the Look AHEAD data, note the marked weight regain after the first year.9 As the comparison data clearly show, while a comprehensive lifestyle intervention can result in a large 1 year weight loss, in the long run testosterone therapy results in a 4 to 8-fold greater weight loss, with no sign of weight regain.

Further, in sex-specific analysis of the Look AHEAD data, differences in fat mass in men in the lifestyle intervention and control groups were not significant at year 8.9 In stark contrast, testosterone therapy results in a progressively continuous weight loss, as well as waist loss, as evidenced by the study by Saad et al. The large reduction in waist circumference suggests that the weight loss was due mostly to a reduction in fat mass, and not lean body mass. Loss of lean body mass is the main drawback with calorie restricted diets, as shown in The Look AHEAD trial.9 As testosterone therapy is well-documented to increase lean body mass43, testosterone therapy in obese hypogonadal men as a novel form of obesity treatment may confer greater beneficial effects on body composition than diet/exercise and/or drug induced weight loss. This, coupled with the correction of testosterone deficiency and its detrimental consequences, will in turn further enhance the health benefits.